Synthesizing 68 primary studies and reviews (PubMed/Scopus/Web of Science, 2000–2026), this narrative review maps the molecular architecture of the muscle-brain axis in aging, identifying irisin/FNDC5, BDNF, IL-6, IGF-1, cathepsin B, and GDF-15 as the key myokine signals disrupted when sarcopenia sets in. The PGC-1α/FNDC5/BDNF pathway emerges as the central exercise-responsive neuroprotective circuit, while chronic IL-6 elevation and declining IGF-1 operate as bidirectional amplifiers of both muscle atrophy and neurodegeneration. Mitochondrial dysfunction, neuromuscular junction instability, inflammaging, and anabolic resistance are identified as shared pathophysiological substrates.
The muscle-brain crosstalk concept is not new — exercise-induced BDNF elevation has been documented since the early 2000s — but this review's strength lies in integrating the full myokine secretome with concrete intervention targets. The AMPK/PGC-1α/SIRT1 axis in particular is attracting pharmacological interest, with metformin and NAD+ precursors already in human trials for aging. Practically, the convergent evidence reinforces leucine-enriched protein timing alongside resistance training as the most evidence-graded dual intervention for preserving both muscle mass and cognitive function in adults over 60. Critical limitations acknowledged here are substantial: most mechanistic evidence remains rodent-derived, no validated human myokine biomarker panel exists, and assay protocols are unstandardized across studies. This is confirmatory-to-integrative work rather than paradigm-shifting — but it usefully consolidates a fragmented literature and sharpens the translational roadmap for biogerontological trials.
